曲贝替定联合度伐利尤单抗治疗晚期经治软组织肉瘤和卵巢癌患者（TRAMUNE）：一项开放标签、多中心Ib期研究。
Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study.
作者信息
Toulmonde Maud, Brahmi Mehdi, Giraud Antoine, Chakiba Camille, Bessede Alban, Kind Michèle, Toulza Emilie, Pulido Marina, Albert Sabrina, Guégan Jean-Philippe, Cousin Sophie, Mathoulin-Pelissier Simone, Perret Raul, Croce Sabrina, Blay Jean-Yves, Ray-Coquard Isabelle, Floquet Anne, Italiano Antoine
机构信息
Department of Medicine, Institut Bergonié, Bordeaux, France.
Department of Medicine, Centre Léon Bérard, Lyon, France.
出版信息
Clin Cancer Res. 2022 May 2;28(9):1765-1772. doi: 10.1158/1078-0432.CCR-21-2258.
PURPOSE
Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models.
PATIENTS AND METHODS
TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses.
RESULTS
A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma.
CONCLUSIONS
Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745.
目的
在临床前模型中，曲贝替定已显示出与免疫检查点抑制剂的协同作用。
患者和方法
TRAMUNE是一项Ib期研究，通过剂量递增阶段和两个扩展队列（软组织肉瘤[STS]和卵巢癌）研究曲贝替定与度伐利尤单抗的联合应用。曲贝替定在第1天以三个剂量水平（1mg/m²、1.2mg/m²和1.5mg/m²）给药，与度伐利尤单抗联合，度伐利尤单抗在第2天给药1120mg，每3周一次。主要终点是曲贝替定与度伐利尤单抗联合应用的推荐II期剂量（RP2D）以及根据RECIST 1.1标准的客观缓解率（ORR）。次要终点包括安全性、6个月无进展率（PFR）、无进展生存期（PFS）、总生存期和生物标志物分析。
结果
共纳入40例患者（剂量递增组，n = 9；STS队列，n = 16；卵巢癌队列，n = 15，80%铂耐药/难治）。最常见的毒性反应为1-2级疲劳、恶心、中性粒细胞减少以及丙氨酸/天冬氨酸转氨酶升高。1例患者在剂量水平2出现剂量限制性毒性。选择1.2mg/m²作为RP2D。在STS队列中，43%的患者出现肿瘤缩小，ORR为7%[95%置信区间（CI），0.2-33.9]，6个月PFR为28.6%（95%CI，8.4-58.1）。在卵巢癌队列中，43%的患者出现肿瘤缩小，ORR为21.4%（95%CI，4.7-5），6个月PFR为42.9%（95%CI，17.7-71.1）。程序性死亡配体1表达和CD8阳性T细胞浸润的基线水平与卵巢癌患者的PFS相关。
结论
曲贝替定与度伐利尤单抗联合应用耐受性良好。在铂难治性卵巢癌患者中观察到有前景的活性。见Digklia等人的相关评论，第1745页。
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